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Biallelic pathogenic variants in INPP5K have been associated with a rare congenital muscular dystrophy that presents with muscle weakness, short stature, intellectual disability, and early-onset cataracts. A characteristic pattern of muscle involvement has been identified on muscle MRI in a small case series, including involvement of the vasti, anterior tibialis, and peronei with relative sparing of the rectus femoris, sartorius, and gracilis muscles. This case describes a patient who initially presented in infancy with hypotonia, motor delays, and short stature. She was eventually diagnosed at almost 3 years with INPP5K -related muscular dystrophy after extensive workup that included multiple subspecialist evaluations, genetic testing for non-neuromuscular disorders, and a muscle biopsy. Muscle ultrasound (MUS) was performed at the end of this diagnostic journey, which demonstrated characteristic features that supported the diagnosis, including notable involvement of the vasti muscles with sparing of the rectus femoris. This case highlights how MUS can be a useful tool in the evaluation of children for neuromuscular disorders. MUS can help refine the differential and guide further steps in evaluation when performed early in the diagnostic process and may help clarify interpretation of genetic testing results when performed later.

Technetium-99m-methoxy isobutyl isonitrile ( 99m Tc-MIBI) myocardial perfusion imaging (MPI) is a functional imaging method with relatively poor specificity but high sensitivity. We present 48-year-old man with cardiac involvement due to muscular dystrophies (MD). Myocardial perfusion imaging rest images revealed regional myocardial perfusion decrease in multiple walls, enlarged heart and decreased left ventricular systolic function. The lesion location of MPI was consistent with that seen on CMR. Our case showed MPI was useful for detection and evaluation of the MD patient with cardiac involvement. In addition, imaging findings in combination with clinical history and other data are important. The case highlight is thevalue of MPI in myocardiopathy.

We report three siblings from a non-consanguineous family presenting with contractural limb-girdle phenotype with intrafamilial variability. Muscle MRI showed posterior thigh and quadriceps involvement with a sandwich-like sign. Whole-exome sequencing identified two compound heterozygous missense TTN variants and one heterozygous LAMA2 variant. Brain MRI performed because of concentration difficulties in one of the siblings evidenced white-matter abnormalities, subsequently found in the others. The genetic analysis was re-oriented, revealing a novel pathogenic intronic LAMA2 variant which confirmed the LAMA2-RD diagnosis. This work highlights the importance of a thorough clinical phenotyping and the importance of brain imaging, in order to orientate and interpret the genetic analysis.

Purpose: In advanced muscular dystrophies (AMD), quantification of muscle echo-intensity (EI) may be influenced by ultrasound beam attenuation, due to fibrosis and fatty infiltration of muscle tissue. Objective of the study was to compare EI measurements using grayscale analysis between a superficial and whole-muscle region of interest (ROI) in subjects with advanced and mild-to-moderate muscular dystrophy (MMD)., Methods: Thirty-two adult subjects diagnosed with a muscular dystrophy and twenty-five matched healthy controls underwent ultrasound assessment of the biceps brachii (BB), rectus femoris (RF) and tibialis anterior (TA) muscles. Based on Heckmatt grading scale of muscles, two disease groups, an AMD (Heckmatt grades 3 or 4) and a MMD (Heckmatt grade 2), were analyzed. Superficial ROI was set as one-fourth of the whole-muscle area, located immediately below the superficial fascia and always inside muscle boundaries., Results: Muscle EI was significantly higher in the superficial compared to whole-muscle ROI, in all evaluated muscle groups of AMD subjects (BB, p = 0.004/RF, p = 0.027/TA, p = 0.002). EI values in superficial ROIs, for individual muscle analysis using z-scores, were more representative in assessments of muscle abnormality in advanced stages of the disease course (Heckmatt grades 3 and 4). In MMD and healthy muscles, no statistical difference was found in EI measurements between the two ROI types., Conclusions: In AMD, selection of superficial ROI is better representative of changes in muscle texture, although caution should be exercised when comparing ROIs of different sizes., (© 2022 Wiley Periodicals LLC.)

Background: LAMA2-related muscular dystrophy (LAMA2-RD) encompasses a group of recessive muscular dystrophies caused by mutations in the LAMA2 gene, which codes for the alpha-2 chain of laminin-211 (merosin). Diagnosis is straightforward in the classic congenital presentation with no ambulation and complete merosin deficiency in muscle biopsy, but is far more difficult in milder ambulant individuals with partial merosin deficiency., Objective: To investigate the diagnostic utility of muscle imaging in LAMA2-RD using whole-body magnetic resonance imaging (WBMRI)., Results: 27 patients (2-62 years, 21-80% with acquisition of walking ability and 6 never ambulant) were included in an international collaborative study. All carried two pathogenic mutations, mostly private missense changes. An intronic variant (c.909 + 7A > G) was identified in all the Chilean cases. Three patients (two ambulant) showed intellectual disability, epilepsy, and brain structural abnormalities. WBMRI T1w sequences or T2 fat-saturated images (Dixon) revealed abnormal muscle fat replacement predominantly in subscapularis, lumbar paraspinals, gluteus minimus and medius, posterior thigh (adductor magnus, biceps femoris, hamstrings) and soleus. This involvement pattern was consistent for both ambulant and non-ambulant patients. The degree of replacement was predominantly correlated to the disease duration, rather than to the onset or the clinical severity. A "COL6-like sandwich sign" was observed in several muscles in ambulant adults, but different involvement of subscapularis, gluteus minimus, and medius changes allowed distinguishing LAMA2-RD from collagenopathies. The thigh muscles seem to be the best ones to assess disease progression., Conclusion: WBMRI in LAMA2-RD shows a homogeneous pattern of brain and muscle imaging, representing a supportive diagnostic tool., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Dermatomyositis (DM) and muscular dystrophy are clinically difficult to differentiate., Purpose: To confirm the feasibility and assess the accuracy of conventional magnetic resonance imaging (MRI), T2 map, diffusion tensor imaging (DTI), and diffusion kurtosis imaging (DKI) in the differentiation of DM from muscular dystrophy., Material and Methods: Forty-two patients with DM proven by diagnostic criteria were enrolled in the study along with 23 patients with muscular dystrophy. Conventional MR, T2 map, DTI, and DKI images were obtained in the thigh musculature for all patients. Intramuscular T2 value, apparent diffusion coefficient (ADC), fractional anisotropy (FA), mean diffusivity (MD), and mean kurtosis (MK) values were compared between the patients with DM and muscular dystrophy. Student's t-tests and receiver operating characteristic (ROC) curve analyses were performed for all parameters. P values < 0.05 were considered statistically significant., Results: The intramuscular T2, ADC, FA, MD, and MK values within muscles were statistically significantly different between the DM and muscular dystrophy groups ( P <0.01). The MK value was statistically significantly different between the groups in comparison with T2 and FA value. As a supplement to conventional MRI, the parameters of MD and MK differentiated DM and muscular dystrophy may be valuable. The optimal cut-off value of ADC and MD values (with respective AUC, sensitivity, and specificity) between DM and muscular dystrophy were 1.698 ×10 -3 mm 2 /s (0.723, 54.1%, and 78.1%) and 1.80 ×10 -3 mm 2 /s (61.9% and 70.2%), respectively., Conclusion: Thigh muscle ADC and MD parameters may be useful in differentiating patients with DM from those with muscular dystrophy.

Objective: To investigate the diagnostic value of implementing a stepwise genetic testing strategy (SGTS) in genetically unsolved cases with dystrophinopathies., Methods: After routine genetic testing in 872 male patients with highly suspected dystrophinopathies, we identified 715 patients with a pathogenic DMD variant. Of the 157 patients who had no pathogenic DMD variants and underwent a muscle biopsy, 142 patients were confirmed to have other myopathies, and 15 suspected dystrophinopathies remained genetically undiagnosed. These 15 patients underwent a more comprehensive evaluation as part of the SGTS pipeline, which included the stepwise analysis of dystrophin mRNA, short-read whole-gene DMD sequencing, long-read whole-gene DMD sequencing and in silico bioinformatic analyses., Results: SGTS successfully yielded a molecular diagnosis of dystrophinopathy in 11 of the 15 genetically unsolved cases. We identified 8 intronic and 2 complex structural variants (SVs) leading to aberrant splicing in 10 of 11 patients, of which 9 variants were novel. In one case, a molecular defect was detected on mRNA and protein level only. Aberrant splicing mechanisms included 6 pseudoexon inclusions and 4 alterations of splice sites and splicing regulatory elements. We showed for the first time the exonisation of a MER48 element as a novel pathogenic mechanism in dystrophinopathies., Conclusion: Our study highlights the high diagnostic utility of implementing a SGTS pipeline in dystrophinopathies with intronic variants and complex SVs., Competing Interests: Competing interests: JY and LZ are employees of Beijing Epigen Medical Technology Inc. Both of them conducted the experiments of dystrophin cDNA analysis., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Merosin-deficient or LAMA2-related congenital muscular dystrophy (CMD) belongs to a group of muscle diseases with an overlapping diagnostic spectrum. MRI plays an important role in the diagnosis and disease-tracking of muscle diseases. Whole-body MRI is ideal for describing patterns of muscle involvement. We intended to analyze the pattern of muscle involvement in merosin-deficient CMD children employing whole-body muscle MRI. Ten children with merosin-deficient CMD underwent whole-body muscle MRI. Eight of which were genetically-confirmed. We used a control group of other hereditary muscle diseases, which included 13 children (mean age was 13 SD +/- 5.5 years), (8 boys and 5 girls) for comparative analysis. Overall, 37 muscles were graded for fatty infiltration using Mercuri scale modified by Fischer et al. The results showed a fairly consistent pattern of muscle fatty infiltration in index group, which differs from that in control group. There was a statistically significant difference between the two groups in regard to the fatty infiltration of the neck, serratus anterior, intercostal, rotator cuff, deltoid, triceps, forearm, gluteus maximus, gluteus medius, gastrocnemius and soleus muscles. Additionally, the results showed relative sparing of the brachialis, biceps brachii, gracilis, sartorius, semitendinosus and extensor muscles of the ankle in index group, and specific texture abnormalities in other muscles. There is evidence to suggest that whole-body muscle MRI can become a useful contributor to the differential diagnosis of children with merosin deficient CMD. The presence of a fairly characteristic pattern of involvement was demonstrated. MRI findings should be interpreted in view of the clinical and molecular context to improve diagnostic accuracy., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose of Review: This review aims to outline the utility of cardiac magnetic resonance (CMR) in patients with different types of muscular dystrophies for the assessment of myocardial involvement, risk stratification and in guiding therapeutic decisions., Recent Findings: In patients suffering from muscular dystrophies (MD), even mild initial dysfunction may lead to severe heart failure over a time course of years. CMR plays an increasing role in the diagnosis and clinical care of these patients, mostly due to its unique capability to precisely characterize subclinical and progressive changes in cardiac geometry, function in order to differentiate myocardial injury it allows the identification of inflammation, focal and diffuse fibrosis as well as fatty infiltration. CMR may provide additional information in addition to the physical examination, laboratory tests, ECG, and echocardiography. Further trials are needed to investigate the potential impact of CMR on the therapeutic decision-making as well as the assessment of long-term prognosis in different forms of muscular dystrophies. In addition to the basic cardiovascular evaluation, CMR can provide a robust, non-invasive technique for the evaluation of subclinical myocardial tissue injury like fat infiltration and focal and diffuse fibrosis. Furthermore, CMR has a unique capability to detect the progression of myocardial tissue damage in patients with a preserved systolic function., (© 2021. The Author(s).)

Arrhythmogenic cardiomyopathy (ACM) is a genetic heart muscle disease caused by mutations of desmosomal genes in about 50% of patients. Affected patients may have defective non-desmosomal genes. The ACM phenotype may occur in other genetic cardiomyopathies, cardio-cutaneous syndromes or neuromuscular disorders. A sizeable proportion of patients have non-genetic diseases with clinical features resembling ACM (phenocopies). The identification of biventricular and left-dominant phenotypic variants has made differential diagnosis more difficult because of the broader spectrum of phenocopies which requires a detailed clinical study with appropriate evaluation of most prominent and discriminatory disease features. Conditions that enter into differential diagnosis of ACM include heart muscle diseases affecting the right ventricle, the left ventricle, or both. To confirm a conclusive diagnosis of ACM, these differential possibilities need to be reasonably excluded by an accurate and targeted clinical evaluation. This article reviews the clinical and imaging features of major phenocopies of ACM and provides indications for differential diagnosis. The recent etiologic classification of Arrhythmogenic Cardiomyopathies, whose common denominator is the distinctive phenotype characterized by a hypokinetic and non-dilated ventricle with a large amount of myocardial fibrosis underlying its propensity to generate ventricular arrhythmias is also addressed.

Background: Dystrophinopathies are the most common type of inherited muscular diseases. Muscle biopsy and genetic tests are effective to diagnose the disease but cost much more than primary hospitals can reach. The more available muscle MRI is promising but its diagnostic results highly depends on doctors' experiences. This study intends to explore a way of deploying a deep learning model for muscle MRI images to diagnose dystrophinopathies., Methods: This study collected 2536 T1WI images from 432 cases who had been diagnosed by genetic analysis and/or muscle biopsy, including 148 cases with dystrophinopathies and 284 cases with other diseases. The data was randomly divided into three sets: the data from 233 cases were used to train the CNN model, the data from 97 cases for the validation experiments, and the data from 102 cases for the test experiments. We also validated our models expertise at diagnosing by comparing the model's results on the 102 cases with those of three skilled radiologists., Results: The proposed model achieved 91% (95% CI: 0.88, 0.93) accuracy on the test set, higher than the best accuracy of 84% in radiologists. It also performed better than the skilled radiologists in sensitivity : sensitivities of the models and the doctors were 0.89 (95% CI: 0.85 0.93) versus 0.79 (95% CI:0.73, 0.84; p = 0.190)., Conclusions: The deep model achieved excellent accuracy and sensitivity in identifying cases with dystrophinopathies. The comparable performance of the model and skilled radiologists demonstrates the potential application of the model in diagnosing dystrophinopathies through MRI images.

Oculopharyngodistal myopathy (OPDM) is a rare hereditary muscle disease characterized by progressive distal limb weakness, ptosis, ophthalmoplegia, bulbar muscle weakness and rimmed vacuoles on muscle biopsy. Recently, CGG repeat expansions in the noncoding regions of two genes, LRP12 and GIPC1, have been reported to be causative for OPDM. Furthermore, neuronal intranuclear inclusion disease (NIID) has been recently reported to be caused by CGG repeat expansions in NOTCH2NLC. We aimed to identify and to clinicopathologically characterize patients with OPDM who have CGG repeat expansions in NOTCH2NLC (OPDM&#95;NOTCH2NLC). Note that 211 patients from 201 families, who were clinically or clinicopathologically diagnosed with OPDM or oculopharyngeal muscular dystrophy, were screened for CGG expansions in NOTCH2NLC by repeat primed-PCR. Clinical information and muscle pathology slides of identified patients with OPDM&#95;NOTCH2NLC were re-reviewed. Intra-myonuclear inclusions were evaluated using immunohistochemistry and electron microscopy (EM). Seven Japanese OPDM patients had CGG repeat expansions in NOTCH2NLC. All seven patients clinically demonstrated ptosis, ophthalmoplegia, dysarthria and muscle weakness; they myopathologically had intra-myonuclear inclusions stained with anti-poly-ubiquitinated proteins, anti-SUMO1 and anti-p62 antibodies, which were diagnostic of NIID (typically on skin biopsy), in addition to rimmed vacuoles. The sample for EM was available only from one patient, which demonstrated intranuclear inclusions of 12.6 ± 1.6 nm in diameter. We identified seven patients with OPDM&#95;NOTCH2NLC. Our patients had various additional central and/or peripheral nervous system involvement, although all were clinicopathologically compatible; thus, they were diagnosed as having OPDM and expanding a phenotype of the neuromyodegenerative disease caused by CGG repeat expansions in NOTCH2NLC.

Purpose of Review: The purpose of this review is to critically discuss the use of ultrasound in the evaluation of muscle disorders with a particular focus on the emerging use in inflammatory myopathies., Recent Findings: In myopathies, pathologic muscle shows an increase in echogenicity. Muscle echogenicity can be assessed visually, semi-quantitatively, or quantitatively using grayscale analysis. The involvement of specific muscle groups and the pattern of increase in echogenicity can further point to specific diseases. In pediatric neuromuscular disorders, the value of muscle ultrasound for screening and diagnosis is well-established. It has also been found to be a responsive measure of disease change in muscular dystrophies. In chronic forms of myositis like inclusion body myositis, ultrasound is very suitable for detecting markedly increased echogenicity and atrophy in affected muscles. Acute cases of muscle edema show only a mild increase in echogenicity, which can also reverse with successful treatment. Muscle ultrasound is an important imaging modality that is highly adaptable to study various muscle conditions. Although its diagnostic value for neuromuscular disorders is high, the evidence in myositis has only begun to accrue in earnest. Further systematic studies are needed, especially in its role for detecting muscle edema.

Using MRI, the main aim was to (1) map the pattern of muscle involvement by assessing fat fraction and (2) investigate frequency of target and sandwich signs in 42 muscles of patients with Bethlem myopathy (BM). Fifteen BM patients were included. Results were compared to findings in 8 healthy controls and 50 patients with four other types of muscular dystrophies. All muscles, except one, showed higher fat fraction in BM patients vs healthy controls (p < 0.05) with an overall proximal muscle affection, resembling a limb girdle-like pattern. In moderate patients, the specificity was 90% for the sandwich sign and 98% for the target sign. Sensitivity for both signs was 100%. Twelve BM patients had sandwich sign in other muscles than the vastus lateralis. Muscle strength correlated with fat fraction. Mean fat fraction in the psoas major was 39% in BM patients, which was considerably higher than in 3 of the 4 muscular dystrophy control diseases. The presence of signs in conjunction with severe affection of the psoas major muscle can serve as a diagnostic tool in BM. The high level of STIR lesions in muscles of BM patients warrants further investigations.

Inclusion body myositis is a slowly progressive myopathy, characteristically affecting quadriceps and long finger flexors. Atypical presentations do occur, however, and there is overlap with other myopathies, including inflammatory and hereditary etiologies. This article discusses atypical cases and differential diagnoses and considers the role of imaging and histopathology in differentiating inclusion body myositis., Competing Interests: Disclosure P.M. Machado has received consulting/speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche, and UCB., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: A hitherto undescribed phenotype of early onset muscular dystrophy associated with sensorineural hearing loss and primary ovarian insufficiency was initially identified in 2 siblings and in subsequent patients with a similar constellation of findings. The goal of this study was to understand the genetic and molecular etiology of this condition., Methods: We applied whole exome sequencing (WES) superimposed on shared haplotype regions to identify the initial biallelic variants in GGPS1 followed by GGPS1 Sanger sequencing or WES in 5 additional families with the same phenotype. Molecular modeling, biochemical analysis, laser membrane injury assay, and the generation of a Y259C knock-in mouse were done., Results: A total of 11 patients in 6 families carrying 5 different biallelic pathogenic variants in specific domains of GGPS1 were identified. GGPS1 encodes geranylgeranyl diphosphate synthase in the mevalonate/isoprenoid pathway, which catalyzes the synthesis of geranylgeranyl pyrophosphate, the lipid precursor of geranylgeranylated proteins including small guanosine triphosphatases. In addition to proximal weakness, all but one patient presented with congenital sensorineural hearing loss, and all postpubertal females had primary ovarian insufficiency. Muscle histology was dystrophic, with ultrastructural evidence of autophagic material and large mitochondria in the most severe cases. There was delayed membrane healing after laser injury in patient-derived myogenic cells, and a knock-in mouse of one of the mutations (Y259C) resulted in prenatal lethality., Interpretation: The identification of specific GGPS1 mutations defines the cause of a unique form of muscular dystrophy with hearing loss and ovarian insufficiency and points to a novel pathway for this clinical constellation. ANN NEUROL 2020;88:332-347., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Recently the scientific community has started to view Bethlem myopathy 1 and Ullrich congenital muscular dystrophy as two extremes of a collagen VI-related myopathy spectrum rather than two separate entities, as both are caused by mutations in one of the collagen VI genes. Here we report three individuals in two families who are homozygous for a COL6A3 mutation (c.7447A> G; p.Lys2483Glu), and compare their clinical features with seven previously published cases. Individuals carrying homozygous or compound heterozygous c.7447A> G, (p.Lys2483Glu) mutation exhibit mild phenotype without loss of ambulation, similar to the cases described previously as Collagen VI-related limb-girdle syndrome. The phenotype could arise due to an aberrant assembly of Von Willebrand factor A domains. Based on these data, we propose that c.7447A> G, (p.Lys2483Glu) is a common pathogenic mutation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Tc-99m methylene diphosphonate ([ 99m Tc]MDP) is an in vivo bone imaging agent that also accumulates in injured skeletal muscle cells. The objective of this study was to investigate if [ 99m Tc]MDP could be used to detect muscle injury in the mdx mouse model of Duchenne muscular dystrophy (DMD)., Procedures: Static whole-body single-photon emission computed tomography/computed tomography (CT) scans were acquired at 2 h post-injection of [ 99m Tc]MDP in two cohorts of animals at different sites: one cohort of mice at 6, 15, and 19 weeks of age, and a separate cohort at 16 weeks. The second cohort was also imaged with high-resolution CT at 8 weeks., Results: mdx mice had higher [ 99m Tc]MDP uptake and significantly higher [ 99m Tc]MDP concentrations in muscle than controls., Conclusions: Higher uptake of [ 99m Tc]MDP in muscle of mdx mice agrees with histological reports of muscle calcification in mdx mice, and suggests the potential translational use of [ 99m Tc]MDP imaging for tracking DMD progression and therapeutic response.

Objective: To delineate the epileptic phenotype of LAMA2-related muscular dystrophy (MD) and correlate it with the neuroradiological and muscle biopsy findings, as well as the functional motor phenotype., Methods: Clinical, electrophysiological, neuroradiological, and histopathological data of 25 patients with diagnosis of LAMA2-related MD were analyzed., Results: Epilepsy occurred in 36% of patients with LAMA2-related MD. Mean age at first seizure was 8 years. The most common presenting seizure type was focal-onset seizures with or without impaired awareness. Visual aura and autonomic signs, including vomiting, were frequently reported. Despite a certain degree of variability, bilateral occipital or temporo-occipital epileptiform abnormalities were by far the most commonly observed. Refractory epilepsy was found in 75% of these patients. Epilepsy in LAMA2-related MD was significantly more prevalent in those patients in whom the cortical malformations were more extensive. In contrast, the occurrence of epilepsy was not found to be associated with the patients' motor ability, the size of their white matter abnormalities, or the amount of residual merosin expressed on muscle., Significance: The epileptic phenotype of LAMA2-related MD is characterized by focal seizures with prominent visual and autonomic features associated with EEG abnormalities that predominate in the posterior quadrants. A consistent correlation between epileptic phenotype and neuroimaging was identified, suggesting that the extension of the polymicrogyria may serve as a predictor of epilepsy occurrence., (© 2020 International League Against Epilepsy.)

Case: An 18-year-old man with Ullrich congenital muscular dystrophy (UCMD) noted difficulty of looking forward and discomfort swallowing and breathing because of his hyperextended neck. We treated his cervical deformity with posterior spinal correction and fusion alone. He underwent a tracheotomy because of lung function deterioration 2 years after cervical surgery. The tracheotomy was performed safely because the anterior cervical spine anatomy was normalized and soft tissues around trachea were preserved by the posterior cervical correction., Conclusion: Cervical hyperextension can be a problem in patients with UCMD. Posterior spinal correction and fusion may be a preferable solution.

Objective: Genetic diagnosis of muscular dystrophies (MDs) has classically been guided by clinical presentation, muscle biopsy, and muscle MRI data. Muscle MRI suggests diagnosis based on the pattern of muscle fatty replacement. However, patterns overlap between different disorders and knowledge about disease-specific patterns is limited. Our aim was to develop a software-based tool that can recognize muscle MRI patterns and thus aid diagnosis of MDs., Methods: We collected 976 pelvic and lower limbs T1-weighted muscle MRIs from 10 different MDs. Fatty replacement was quantified using Mercuri score and files containing the numeric data were generated. Random forest supervised machine learning was applied to develop a model useful to identify the correct diagnosis. Two thousand different models were generated and the one with highest accuracy was selected. A new set of 20 MRIs was used to test the accuracy of the model, and the results were compared with diagnoses proposed by 4 specialists in the field., Results: A total of 976 lower limbs MRIs from 10 different MDs were used. The best model obtained had 95.7% accuracy, with 92.1% sensitivity and 99.4% specificity. When compared with experts on the field, the diagnostic accuracy of the model generated was significantly higher in a new set of 20 MRIs., Conclusion: Machine learning can help doctors in the diagnosis of muscle dystrophies by analyzing patterns of muscle fatty replacement in muscle MRI. This tool can be helpful in daily clinics and in the interpretation of the results of next-generation sequencing tests., Classification of Evidence: This study provides Class II evidence that a muscle MRI-based artificial intelligence tool accurately diagnoses muscular dystrophies., (© 2020 American Academy of Neurology.)

Mutations in collagen VI genes cause two major clinical myopathies, Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), and the rarer myosclerosis myopathy. In addition to congenital muscle weakness, patients affected by collagen VI-related myopathies show axial and proximal joint contractures, and distal joint hypermobility, which suggest the involvement of tendon function. To gain further insight into the role of collagen VI in human tendon structure and function, we performed ultrastructural, biochemical, and RT-PCR analysis on tendon biopsies and on cell cultures derived from two patients affected with BM and UCMD. In vitro studies revealed striking alterations in the collagen VI network, associated with disruption of the collagen VI-NG2 (Collagen VI-neural/glial antigen 2) axis and defects in cell polarization and migration. The organization of extracellular matrix (ECM) components, as regards collagens I and XII, was also affected, along with an increase in the active form of metalloproteinase 2 (MMP2). In agreement with the in vitro alterations, tendon biopsies from collagen VI-related myopathy patients displayed striking changes in collagen fibril morphology and cell death. These data point to a critical role of collagen VI in tendon matrix organization and cell behavior. The remodeling of the tendon matrix may contribute to the muscle dysfunction observed in BM and UCMD patients., Competing Interests: The authors declare no conflicts of interest.

Collagen VI-related dystrophies (COL6-RDs) and Duchenne muscular dystrophy (DMD) cause progressive muscle weakness and disability. COL6-RDs are caused by mutations in the COL6 genes (COL6A1, COL6A2 and COL6A3) encoding the extracellular matrix protein collagen VI, and DMD is caused by mutations in the DMD gene encoding the cytoplasmic protein dystrophin. Both COL6-RDs and DMD are characterized by infiltration of the muscles by fatty and fibrotic tissue. This study examined the effect of disease pathology on skeletal muscles in lower extremity muscles of COL6-RDs using timed functional tests, strength measures and qualitative/ quantitative magnetic resonance imaging/spectroscopy measures (MRI/MRS) in comparison to unaffected (control) individuals. Patients with COL6-RD were also compared to age and gender matched patients with DMD.Patients with COL6-RD presented with a typical pattern of fatty infiltration of the muscle giving rise to an apparent halo effect around the muscle, while patients with DMD had evidence of fatty infiltration throughout the muscle areas imaged. Quantitatively, fat fraction, and transverse relaxation time (T2) were elevated in both COL6-RD and DMD patients compared to unaffected (control) individuals. Patients with COL6-RD had widespread muscle atrophy, likely contributing to weakness. In contrast, patients with DMD revealed force deficits even in muscle groups with increased contractile areas.

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

Background: Dystrophin-glycoprotein complex (DGC)-related muscular dystrophies may present similar clinical and pathological features as well as undetectable mutations thus being sometimes difficult to distinguish. We investigated the value of muscle magnetic resonance imaging (MRI) in the differential diagnosis of DGC-related muscular dystrophies and reported the largest series of Chinese patients with sarcoglycanopathies studied by muscle MRI., Results: Fifty-five patients with DGC-related muscular dystrophies, including 22 with confirmed sarcoglycanopathies, 11 with limb-girdle muscular dystrophy 2I (LGMD2I, FKRP-associated dystroglycanopathy), and 22 with dystrophinopathies underwent extensive clinical evaluation, muscle biopsies, genetic analysis, and muscle MRI examinations. Hierarchical clustering of patients according to the clinical characteristics showed that patients did not cluster according to the genotypes. No statistically significant differences were observed between sarcoglycanopathies and LGMD2I in terms of thigh muscle involvement. The concentric fatty infiltration pattern was observed not only in different sarcoglycanopathies (14/22) but also in LGMD2I (9/11). The trefoil with single fruit sign was observed in most patients with dystrophinopathies (21/22), and a few patients with sarcoglycanopathies (4/22) or LGMD2I (2/11). Hierarchical clustering showed that most patients with sarcoglycanopathies or LGMD2I can be distinguished from dystrophinopathies based on the concentric fatty infiltration pattern and trefoil with single fruit sign at the thigh level on muscle MRI., Conclusions: Muscle MRI at the thigh level potentially allows distinction of sarcoglycanopathies or FKRP-associated dystroglycanopathy from dystrophinopathies.

Background: Mercuri grading of muscle images is a useful method to evaluate the progression of muscular dystrophies. However, because Mercuri grading is skill-based, few competent experts are available. We therefore developed an automated method for Mercuri grade calculations., Methods: We used computed tomography (CT) and magnetic resonance (MR) images of the thigh and lower leg muscles taken from a Japanese limb-girdle muscular dystrophy patient database. We calculated muscle impairment ratios based on the CT images, and then converted the ratios to revised Mercuri grades. This method was also applied to T1-weighted MR images. Additionally, radiation absorption doses in muscle and chest CT images from a separate patient group were also analyzed., Results: We observed a close correlation between our automatically calculated Mercuri grades and skill-based visually determined Mercuri grades in both CT and MR images. The radiation absorption, measured by total dose length product, was lower in muscle CT (121.8 mGy-cm) than in chest CT (524.1 mGy-cm)., Conclusions: We developed a new automatic Mercuri grading method using values obtained from CT images. This method was also applied to calculate the Mercuri grade of T1-weighted MR images. In addition, the radiation doses from muscle CT were observed to be lower than those from chest CT., (Copyright © 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Recent years have seen steady progress in the identification of genetic muscle diseases as well as efforts to develop treatment for these diseases. Consequently, sensitive and objective new methods are required to identify and monitor muscle pathology. Magnetic resonance imaging offers multiple potential biomarkers of disease severity in the muscular dystrophies. This Review uses a pathology-based approach to examine the ways in which MRI and spectroscopy have been used to study muscular dystrophies. Methods that have been used to quantitate intramuscular fat, edema, fiber orientation, metabolism, fibrosis, and vascular perfusion are examined, and this Review describes how MRI can help diagnose these conditions and improve upon existing muscle biomarkers by detecting small increments of disease-related change. Important challenges in the implementation of imaging biomarkers, such as standardization of protocols and validating imaging measurements with respect to clinical outcomes, are also described., (© 2019 Wiley Periodicals, Inc.)

Objective: To determine the safety and effectiveness of the combined halo gravity traction and dual growing rod technique in achieving and maintaining scoliosis correction while allowing spinal growth., Methods: From January 2014 to July 2017, 11 patients with dystrophic neurofibromatosis type 1 (NF1)-associated scoliosis, including 7 men and 4 women, underwent combined halo gravity traction and dual growing rod technique procedures. Diagnoses were all dystrophic NF1-associated scoliosis. Patients with a Cobb angle of major curve >60° and flexibility of spine <30% were included in our research. Analysis included age at the time of treatment, levels of instrumentation, number and frequency of lengthening, lengthening distance, and complications. The changes in Cobb angle of scoliosis and T1-S1 length of spine over the treatment period were measured by radiographic evaluation., Results: The average age of treated patients was 7.2 years (range, 5-9 years). Growing rods were lengthened every 6 months through exposure. The mean number of times of lengthening was 3.9 (range, 3-5). The distance of each extension was 1.6 cm (range, 1.0-2.0 cm). The Cobb angle was corrected 41.7% on average after traction, 48.4% after initial surgery, and 53.3% at the last follow-up. T1-S1 length increased 3.4 cm (range, 1.2-5.1 cm) on average over a mean treatment period of 2.2 years, with an average of 1.5 cm/y (range, 0.5-2.3 cm/y). During the treatment period, complication of hook dislodgement occurred in 1 of 11 patients (9.1%)., Conclusions: The combined halo gravity traction and dual growing rod technique can safely and effectively correct NF1-associated scoliosis. This is an ongoing study that requires long-term follow-up., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Recessive mutations in the MSTO1 gene, encoding for a mitochondrial distribution and morphology regulator, have been recently described in a very limited number of patients with multisystem involvement, mostly characterized by myopathy or dystrophy, cerebellar ataxia, pigmentary retinopathy and raised creatine kinase levels. Here we report an additional patient with recessive MSTO1-related muscular dystrophy (MSTO1-RD), and clinical and radiological evidence of progressive cerebellar involvement. Whole-exome sequencing identified two novel MSTO1 missense variants, c.766C > T (p. (Arg256Trp) and c.1435C > T (p. (Pro479Ser), predicted as damaging by in silico tools. We also report a distinct pattern of selective involvement on muscle MRI in MSTO1-RD. This case confirms a consistent MSTO1-related neuromuscular phenotype and in addition suggests a progressive neurological component at least in some patients, in keeping with the mitochondrial role of the defective protein., (Copyright © 2019. Published by Elsevier B.V.)

Background: Bethlem myopathy represents the milder phenotype of collagen type VI-related myopathies. However, clinical manifestations are highly variable among patients and no phenotype-genotype correlation has been described. We aim to analyse the clinical, pathological and genetic features of a series of patients with Bethlem myopathy, and we describe seven new mutations., Methods: A series of 16 patients with the diagnosis of Bethlem myopathy were analyzed retrospectively from their medical records for clinical, creatine kinase (CK), muscle biopsy, and muscle magnetic resonance (MRI) data. Genetic testing was performed through next-generation sequencing of custom amplicon-based targeted genes panel of myopathies. Mutations were confirmed by Sanger sequencing., Results: The most frequent phenotype consisted of proximal limb weakness associated with interphalangeal and wrists contractures. However, cases with isolated contractures or isolated myopathy were found. CK levels did not correlate with severity of the disease. The most frequent mutation was the COL6A3 variant c.7447A>G, p.Lys2486Glu, with either an homozygous or compound heterozygous presentation. Five new mutations were found in COL6A1 gene and other two in COL6A3 gene, all of them with a dominant heritability pattern. From these, a new COL6A1 mutation (c.1657G>A, p.Glu553Arg) was related to an oligosymptomatic phenotype with predominating contractures in the absence of weakness and a normal muscle MRI. Finally, the most common COL6A1 mutation reported to date that leads to an Ullrich phenotype (c. 868G>A, p.Gly290Arg), has been found here as Bethlem presentation., Conclusions: Manifestations of Bethlem myopathy are quite variable, so either contractures or weakness may be lacking, and no phenotype-genotype associations can be brought.

Morphological characteristics of muscle fibers, such as their cross-sections, are important indicators of the health and function of the musculoskeletal system. However, manual analysis of muscle fiber morphology is a labor-intensive and time-consuming process that is prone to errors. Overall, the procedure involves high inter- and intra-observer variability. Therefore, it is desirable for biologists to have a tool that can produce objective and reproducible analysis for muscle fiber images. In this work, we propose a deep convolutional neural network (DCNN) followed by post-processing for detecting and measuring the cross-sections of muscle fibers. We evaluate three segmentation networks for muscle boundary segmentation: (1) U-net, (2) FusionNet, and (3) a customized FusionNet. The customized FusionNet, which had the highest Dice coefficient on the test set, was used for subsequent morphological analysis of the muscle fibers. The proposed method was tested on microscopic images of the tibialis anterior muscles of a pre-clinical model of muscular dystrophy. The dataset contained four mosaic images, totalling more than 3400 fibers. Because of the severity of muscle injury in this pre-clinical model, its muscle fiber images present a challenge for quantitative analysis for several reasons. First, the muscle fibers had inhomogeneous spatial distribution and very different sizes. Second, the membranes of the muscle fibers had uneven signal intensity due to the loss of a membrane protein. Third, the shapes of intact muscle fibers were very different. All these factors contributed to the difficulty of acquiring good training data in the first place. Despite these difficulties, we achieved an average muscle fiber overlay precision of 0.65 and an average recall of 0.49. In this context, overlaid fibers are defined as fibers that have one or more pixels overlaying in the manual and DCNN cross-section segmentation. For the overlaid fibers, the proposed method achieved excellent segmentation accuracy of 94% ± 10.26%, as measured by the Dice-Sorensen coefficient., (Copyright © 2018. Published by Elsevier Ltd.)

Hereditary muscular diseases commonly involve the heart. Cardiac manifestations encompass a spectrum of phenotypes, including both cardiomyopathies and rhythm disorders. Common biomarkers suggesting cardiomuscular diseases include increased circulating creatine kinase and/or lactic acid levels or disease-specific metabolic indicators. Cardiac and extra-cardiac traits, imaging tests, family studies, and genetic testing provide precise diagnoses. Cardiac phenotypes are mainly dilated and hypokinetic in dystrophinopathies, Emery-Dreifuss muscular dystrophies, and limb girdle muscular dystrophies; hypertrophic in Friedreich ataxia, mitochondrial diseases, glycogen storage diseases, and fatty acid oxidation disorders; and restrictive in myofibrillar myopathies. Left ventricular noncompaction is variably associated with the different myopathies. Conduction defects and arrhythmias constitute a major phenotype in myotonic dystrophies and skeletal muscle channelopathies. Although the actual cardiac management is rarely based on the cause, the cardiac phenotypes need precise characterization because they are often the only or the predominant manifestations and the prognostic determinants of many hereditary muscle disorders., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

In this study, multi-parametric magnetic resonance imaging (MRI) was conducted to monitor skeletal muscle changes in dystrophic (mdx4cv) and age-matched control (C57BL/6J) mice starting at 3 weeks of age. The objective of this study was to evaluate and characterize changes in muscle tissue characteristics of hind limbs in young, dystrophic mice using MRI. Mdx4cv (n = 25) and age-matched C57BL/6J (n = 5) were imaged at 3, 5, 7, 9, and 11 weeks of age. Multiple MR measurements were taken from the tibialis anterior, gastrocnemius, and soleus muscles. There were significant differences between dystrophic and control groups for all three muscle types when comparing transverse relaxation times (T2) in lower hind limb muscles. Additionally, fractional anisotropy, radial diffusivity, and eigenvalue analysis of diffusion tensor imaging also demonstrated significant differences between groups. Longitudinal relaxation times (T1) displayed no significant differences between groups. The earliest time points in the magnetization transfer ratio measurements displayed a significant difference. Histological analysis revealed significant differences in the tibialis anterior and gastrocnemius muscles between groups with the mdx mice displaying greater variability in muscle fiber size in later time points. The multi-parametric MRI approach offers a promising alternative for future development of a noninvasive avenue for tracking both disease progression and treatment response., Competing Interests: The authors have declared that no competing interests exist.

A 38-year-old woman presented with extreme fatigue and multiple lung nodules. She was referred for a PET/CT, which demonstrated multiple FDG-avid pulmonary nodules and lymph nodes with intense uptake within multiple muscle groups predominantly involving the paraspinal muscles and muscles of mastication. Histopathology of a paraspinal muscle biopsy revealed increased skeletal muscle lipid stores and increased mitochondria with normal morphology. This abnormality is seen in metabolic myopathy due to a disorder of fatty acid oxidation. Transbronchial biopsy showed no evidence of sarcoidosis. The patient was commenced on carnitine and riboflavin supplementation, and a follow-up PET/CT was performed.

Objective: To describe a large series of BIN1 patients, in which a novel founder mutation in the Roma population of southern Spain has been identified., Methods: Patients diagnosed with centronuclear myopathy (CNM) at 5 major reference centers for neuromuscular disease in Spain (n = 53) were screened for BIN1 mutations. Clinical, histologic, radiologic, and genetic features were analyzed., Results: Eighteen patients from 13 families carried the p.Arg234Cys variant; 16 of them were homozygous for it and 2 had compound heterozygous p.Arg234Cys/p.Arg145Cys mutations. Both BIN1 variants have only been identified in Roma, causing 100% of CNM in this ethnic group in our cohort. The haplotype analysis confirmed all families are related. In addition to clinical features typical of CNM, such as proximal limb weakness and ophthalmoplegia, most patients in our cohort presented with prominent axial weakness, often associated with rigid spine. Severe fat replacement of paravertebral muscles was demonstrated by muscle imaging. This phenotype seems to be specific to the p.Arg234Cys mutation, not reported in other BIN1 mutations. Extreme clinical variability was observed in the 2 compound heterozygous patients for the p.Arg234Cys/p.Arg145Cys mutations, from a congenital onset with catastrophic outcome to a late-onset disease. Screening of European Roma controls (n = 758) for the p.Arg234Cys variant identified a carrier frequency of 3.5% among the Spanish Roma., Conclusion: We have identified a BIN1 founder Roma mutation associated with a highly specific phenotype, which is, from the present cohort, the main cause of CNM in Spain., (© 2018 American Academy of Neurology.)

Background: LMNA-related muscular dystrophy can manifest in a wide variety of disorders, including Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy (LGMD), and LMNA-associated congenital muscular dystrophy (L-CMD). Muscle magnetic resonance imaging (MRI) has become a useful tool in the diagnostic workup of patients with muscle dystrophies. This study aimed to investigate whether there is a consistent pattern of MRI changes in patients with LMNA mutations in various muscle subtypes., Methods: Twenty-two patients with LMNA-related muscular dystrophies were enrolled in this study. MRI of the thigh and/or calf muscles was performed in them. The muscle MRI features of the three subtypes were compared by the Mann-Whitney U-test. The relationship between the clinical and MRI findings was also investigated by Spearman's rank analyses., Results: The present study included five EDMD, nine LGMD, and eight L-CMD patients. The thigh muscle MRI revealed that the fatty infiltration of the adductor magnus, semimembranosus, long and short heads of the biceps femoris, and vasti muscles, with relative sparing of the rectus femoris, was the predominant change observed in the EDMD, LGMD, and advanced-stage L-CMD phenotypes, although the involvement of the vasti muscles was not prominent in the early stage of L-CMD. At the level of the calf, six patients (one EDMD, four LGMD, and one L-CMD) also showed a similar pattern, in which the soleus and the medial and lateral gastrocnemius muscles were most frequently observed to have fatty infiltration. The fatty infiltration severity demonstrated higher scores associated with disease progression, with a corresponding rate of 1.483 + 0.075 × disease duration (X) (r = 0.444, P = 0.026). It was noteworthy that in six L-CMD patients with massive inflammatory cell infiltration in muscle pathology, no remarkable edema-like signals were observed in muscle MRI., Conclusions: EDMD, LGMD and advanced-staged L-CMD subtypes showed similar pattern of muscle MRI changes, while early-staged L-CMD showed somewhat different changes. Muscle MRI of L-CMD with a muscular dystrophy pattern in MRI provided important clues for differentiating it from childhood inflammatory myopathy. The fatty infiltration score could be used as a reliable biomarker for outcome measure of disease progression., Competing Interests: There are no conflicts of interest

Background: Transport protein particle (TRAPP) is a supramolecular protein complex that functions in localizing proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in muscle disease by virtue of homozygous and compound heterozygous deleterious mutations being identified in individuals with limb girdle muscular dystrophy and congenital muscular dystrophy. It remains unclear how this protein leads to muscle disease. Furthermore, a role for this protein, or any other membrane trafficking protein, in the etiology of the dystroglycanopathy group of muscular dystrophies has yet to be found. Here, using a multidisciplinary approach including genetics, immunofluorescence, western blotting, and live cell analysis, we implicate both TRAPPC11 and another membrane trafficking protein, GOSR2, in α-dystroglycan hypoglycosylation., Case Presentation: Subject 1 presented with severe epileptic episodes and subsequent developmental deterioration. Upon clinical evaluation she was found to have brain, eye, and liver abnormalities. Her serum aminotransferases and creatine kinase were abnormally high. Subjects 2 and 3 are siblings from a family unrelated to subject 1. Both siblings displayed hypotonia, muscle weakness, low muscle bulk, and elevated creatine kinase levels. Subject 3 also developed a seizure disorder. Muscle biopsies from subjects 1 and 3 were severely dystrophic with abnormal immunofluorescence and western blotting indicative of α-dystroglycan hypoglycosylation. Compound heterozygous mutations in TRAPPC11 were identified in subject 1: c.851A>C and c.965+5G>T. Cellular biological analyses on fibroblasts confirmed abnormal membrane trafficking. Subject 3 was found to have compound heterozygous mutations in GOSR2: c.430G>T and c.2T>G. Cellular biological analyses on fibroblasts from subject 3 using two different model cargo proteins did not reveal defects in protein transport. No mutations were found in any of the genes currently known to cause dystroglycanopathy in either individual., Conclusion: Recessive mutations in TRAPPC11 and GOSR2 are associated with congenital muscular dystrophy and hypoglycosylation of α-dystroglycan. This is the first report linking membrane trafficking proteins to dystroglycanopathy and suggests that these genes should be considered in the diagnostic evaluation of patients with congenital muscular dystrophy and dystroglycanopathy.

Background Diffusion tensor imaging (DTI) of peripheral nerves may provide additional information about nerve involvement in muscular disorders, but is considered difficult due to different optimal scan parameters tailored to magnetic resonance (MR) signal properties of muscle and neural tissues. Purpose To assess the feasibility of sciatic nerve DTI using two different approaches of region of interest (ROI)-localization in DTI scans with b-values 500 s/mm 2 , in participants with muscular disorders and in controls. Material and Methods DTI of the thigh was conducted on a 3T system in ten patients (6 men, 4 women; mean age =54 ± 15 years) with neuromuscular disorders and ten controls. T1-weighted (T1W) images were co-registered to fractional anisotropy (FA) color-encoded images. The apparent diffusion coefficient (ADC), FA, and fiber track length (FTL) were analyzed by two operators using a freehand ROI and a single-point ROI covering the sciatic nerve. Interclass correlation coefficient (ICC) and Bland-Altman analysis were used for evaluation of inter-operator and inter-technical agreement, respectively. Results Three-dimensional visualization of sciatic nerve fiber was achievable using both techniques. The ICC of DTI metrics showed excellent inter-operator agreement both in patients and controls. Bland-Altman analysis revealed good agreement of both techniques. A maximum FTL was achieved using the single-point ROI technique, but with a lower inter-operator agreement (ICC = 0.99 vs. 0.83). The ADC and maximum FTL were significantly decreased in patients compared to controls. Conclusion Both ROI localization techniques are feasible to analyze the sciatic nerve in the setting of muscular disease. A maximum FTL is reached using the single-point ROI, however, at the cost of lower inter-operator agreement.

Objectives: COL6A and LAMA2 are subtypes of congenital muscular dystrophy., Methods: Retrospective chart review of clinical findings, spirometry, muscle histology, muscle ultrasound, neuroimaging, and Electromyography (EMG)/Nerve Conduction Study data in genetically confirmed COL6A and LAMA2 subjects., Results: We identified 8 COL6A and 6 LAMA2 subjects: the female-to-male ratio was 1.3:1 and the mean age was 11.9 ± 3.6 years. Gross motor delays since birth, proximal muscle weakness, and contractures were noted in both groups. Joint hyperlaxity and skin changes (follicular hyperkeratosis and muscle biopsy scar thinning) were unique to COL6A. Severe scoliosis, macrocephaly, and nonambulatory status were common in LAMA2. Increasing age was associated with poor respiratory function in COL6A. There was central "cloud appearance" on rectus femoris muscle ultrasound in COL6A and white matter T2 hyperintensity on brain magnetic resonance imaging in LAMA2. LAMA2 also showed demyelinating polyneuropathy. Neurogenic changes on EMG and muscle histology were noted in 37% and 33% of COL6A cases, respectively., Conclusions: COL6A has unique skin changes, central cloud appearance on muscle ultrasound. LAMA2 has demyelinating polyneuropathy and white matter changes on brain imaging. The presence of neurogenic changes on EMG and muscle histology in COL6A suggests motor axonal neuropathy. Genetic testing remains the gold standard in confirming COL6A congenital muscular dystrophy.

Introduction: Bcl-2-associated athanogene-3 (BAG3) mutations have been described in rare cases of rapidly progressive myofibrillar myopathies. Symptoms begin in the first decade with axial involvement and contractures and are associated with cardiac and respiratory impairment in the second decade. Axonal neuropathy has been documented but usually not as a key clinical feature., Methods: We report a 24-year-old woman with severe rigid spine syndrome and sensory-motor neuropathy resembling Charcot-Marie-Tooth disease (CMT)., Results: Muscle MRI showed severe fat infiltration without any specific pattern. Deltoid muscle biopsy showed neurogenic changes and discrete myofibrillar abnormalities. Electrocardiogram and transthoracic echocardiography results were normal. Genetic analysis of a panel of 45 CMT genes showed no mutation. BAG3 gene screening identified the previously reported c.626C>T, pPro209Leu, mutation., Discussion: This case indicates that rigid spine syndrome and sensory-motor axonal neuropathy are key clinical features of BAG3 mutations that should be considered even without cardiac involvement. Muscle Nerve, 57: 330-334, 2018., (© 2017 Wiley Periodicals, Inc.)

Introduction: Immune-mediated necrotizing myopathies (IMNMs) are characterized by progressive weakness, elevated serum creatine kinase levels, and necrotizing myopathic features on muscle biopsy. Presence of highly specific autoantibodies against signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl- coenzyme A reductase (HMGCR) can aid in recognition and confirmation of IMNMs., Methods: In this study we describe a boy with HMGCR-positive necrotizing myopathy and highlight the clinical features of the patient., Results: In contrast to most adults, the patient described had a more indolent disease course, reminiscent of a muscular dystrophy. Intravenous immunoglobulin monotherapy resulted in a dramatic clinical response with return to normal strength., Conclusions: Systematic consideration of IMNMs and testing for relevant autoantibodies in children with suspected but genetically unconfirmed muscular dystrophy may help improve diagnostic accuracy and allow timely treatment with potentially highly effective immunotherapies. Muscle Nerve 56: 175-179, 2017., (© 2017 Wiley Periodicals, Inc.)

Fukuyama congenital muscular dystrophy weakens both skeletal and cardiac muscles, but the rate of cardiomyopathic progression can accelerate faster than that of skeletal muscles. A 14-year-old boy with Fukuyama congenital muscular dystrophy presented with mild skeletal myopathy but severe cardiomyopathy requiring heart transplantation within 1 year of declining heart function. These patients need frequent screening regardless of musculoskeletal symptoms.

The dystroglycanopathies are a heterogeneous group of conditions, with mutations in B3GALNT2 described in association with congenital muscular dystrophy. The serial prenatal MRI findings in this disorder have not been well described. We present sequential prenatal and postnatal MRI findings in a boy with compound heterozygous mutations in B3GALNT2, as well as the MRI findings of his two siblings with similar mutations. These findings provide new insight into the molecular pathogenesis and neurodevelopment of congenital muscular dystrophy.